Spherical 10-phenothiazinylpropanoic acid agglomerates and method for preparing same

ABSTRACT

The present invention relates to novel spherical agglomerates of 10-phenothiazinylpropanoic acid. The invention also relates to a process for obtaining those agglomerates. 
     The process for preparing the spherical agglomerates of 10-phenothiazinylpropanoic acid is characterized by stirring a suspension of 10-phenothiazinylpropanoic acid in water in the presence of a binder liquid which is not miscible with water selected from esters of aliphatic or cycloaliphatic acids, aliphatic or cycloaliphatic alcohols, and aliphatic or cycloaliphatic ketones.

The present invention relates to novel spherical agglomerates of10-phenothiazinylpropanoic acid. The invention also relates to a processfor obtaining those agglomerates.

10-phenothiazinylpropanoic acid is an organic product used as anintermediate in synthesis.

It is represented by the following formula ##STR1##

A method for preparing that product is described by Nathan L., Smith J.in Org. Chem 15, 1125 (1950).

The product obtained is in the form of a precipitate which is difficultto separate by filtering, which necessitates re-crystallisation from anorganic solvent, generally an alcohol.

Further, in many applications, the products used must be in a form inwhich they must satisfy a number of requirements:

the product must be easy to manipulate;

the granulometric distribution of the product must exclude fineparticles which generate dust;

the substance must have good flow properties and must not form lumps intemporary hopper type storage units or during use in a subsequenttransformation process, or during long term storage in the usualpackaging.

In order to satisfy the above requirements, the present inventionprovides a novel presentation of 10-phenothiazinylpropanoic acid and aprocess for obtaining it which can overcome the filtering problem.

More precisely, the present invention provides spherical agglomerates of10-phenothiazinylpropanoic acid.

In the description of the present invention, the term"10-phenothiazinylpropanoic acid" includes3-(10-phenothiazinyl)propanoic acid and similar products, i.e., productsin which the benzene rings of the phenothiazinyl radical carrysubstituents provided that they do not modify the surface properties.Examples which can be cited are low alkyls (C₁ -C₄), halogen atoms or aCF₃ radical.

The term "spherical" agglomerates means solid particles with a highdegree of sphericity.

The process for preparing the spherical agglomerates of10-phenothiazinylpropanoic acid is characterized by stirring asuspension of 10-phenothiazinylpropanoic acid in water in the presenceof a liquid binder which is not miscible with water selected from estersof aliphatic or cycloaliphatic acids, aliphatic or cycloaliphaticalcohols, and aliphatic or cycloaliphatic ketones.

The agglomerates obtained in accordance with the invention havephysicochemical properties which are peculiar to them. The essentiallyspherical particles have a diameter which can vary within a wide range.Size determination is carried out using image analysis.

Generally the particle size, expressed as the medial diameter (d₅₀), isfrom 50 μm to 3000 μm, preferably from 200 μm to 1200 μm and morepreferably between 500 μm and 1000 μm. The medial diameter is defined asthat at which 50% by weight of the particles have a diameter larger orsmaller than the medial diameter.

FIG. 1 shows a photograph of the agglomerates of the invention takenusing a microscope (magnification=16) which shows the spherical shape ofthe particles obtained.

A further characteristic of the agglomerates of the invention is thatthe fines ratio (particles of less than 100 μm) is low, preferably lessthan 0.5%, more preferably less than 0.1%.

In accordance with the process of the invention, spherical agglomeratesof 10-phenothiazinylpropanoic acid are prepared by stirring a suspensionof 10-phenothiazinylpropanoic acid in water in the presence of a liquidbinder which is not miscible with water as defined above.

When selecting the liquid binder, an organic solvent is used in whichthe 10-phenothiazinylpropanoic acid is very slightly soluble, i.e., witha solubility of less than 5%, preferably less than 1%.

The liquid binder, selected from esters of aliphatic or cycloaliphaticacids, aliphatic or cycloaliphatic alcohols, and aliphatic orcycloaliphatic ketones, generally satisfies this requirement when itscarbon condensation is at least 5. There is no upper limit to the numberof carbon atoms provided that the binder remains liquid duringgranulation.

Thus in a variation of the process of the invention, a liquid which maybe solid at ambient temperature (usually between 15° C. and 25° C.) butfusible under the granulation temperature conditions, is used. In thiscase, slight heating may be necessary during the granulation operation.

Particular examples of aliphatic acid esters used are n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, andisopentyl acetates.

Examples of aliphatic alcohols are isopentanol and octanol.

Regarding ketones, a particular example is cyclohexanone.

Of all of the binders cited above n-propyl acetate or isopropyl acetateare preferred.

The starting 10-phenothiazinylpropanoic acid may be a crystalline orground product. The particle size, expressed as the medial diameter(d₅₀), can vary, for example from 1 μm to 100 μm.

The quantity of water with respect to the 10-phenothiazinylpropanoicacid is not critical; however, it is preferable to use suspensionscorresponding to about 400 to 2000 cm³ of water, preferably 800 to 1000cm³ per 100 g of 10-phenothiazinylpropanoic acid.

The mixture is stirred. The type of stirring is not critical, however itis preferable to use shear stirring using a Rushton® type turbine, forexample.

The rate of stirring of the mixture must be sufficient to obtain ahomogeneous suspension of 10-phenothiazinylpropanoic acid in water and ahomogeneous dispersion of liquid binder. A rate of 500 to 800 rpm isgenerally used when operating in a 1 liter reactor.

The quantity of liquid binder with respect to the10-phenothiazinylpropanoic acid is critical. Below a minimum quantity ofliquid binder, there is no agglomeration; in contrast, if too great aquantity of liquid binder is used, the solid particles are dispersed inthe liquid binder and they can easily deform.

For each liquid binder, the proportions between which sphericalagglomerates are formed and remain stable can be carried out as follows.

Liquid binder is added dropwise to a suspension of 100 g of10-phenothiazinylpropanoic acid in 900 cm³ of water which isenergetically stirred (rotation rate 700 rpm). Aliquots of thesuspension are removed during addition and examined to determine theminimum quantity of liquid binder required to form sphericalagglomerates. Liquid binder addition is continued to determine thequantity of liquid beyond which the spherical agglomerates begin todisaggregate.

As an indication, when using an aliphatic ester, the quantity to be usedis advantageously between 0.4 and 0.7 g per g of10-phenothiazinylpropanoic acid.

When using the process of the invention, it is not necessary to addliquid binder gradually; the quantity thereof which is necessary forformation of the spherical agglomerates can be added all at once to thestirred aqueous suspension of 10-phenothiazinylpropanoic acid.

In general, the spherical agglomerates form a few minutes after addingthe liquid binder. The diameter of the agglomerates then increasesapproximately linearly with respect to the period of stirring thenremains practically constant. It is thus possible to stop the growth ofthe agglomerates when they have reached the desired dimensions.

The spherical agglomerates can be separated from the formation mediumusing conventional solid/liquid separation techniques, preferably byfiltering.

The constituents (water and liquid binder) of the liquid phase can beseparated, for example by azeotropic distillation, and recycled tosubsequent operations.

In accordance with the invention, it should be noted that the size ofthe agglomerates can be increased, after the agglomeration step andbefore the solid/liquid separation step, by adding a supplemental amountof 10-phenothiazinylpropanoic acid in suspension in water or by adding asupplemental amount of powdered 10-phenothiazinylpropanoic acid to thestirred medium containing the agglomerates. Solid10-phenothiazinylpropanoic acid affixes itself to the surface of theformed grains and thus coats them with a solid layer. The quantity of10-phenothiazinylpropanoic acid added can be 5% to 50% by weight ofinitially agglomerated the 10-phenothiazinylpropanoic acid.

The agglomerates obtained using the process of the invention can then bedried using conventional techniques which are known to the skilledperson. Drying is generally carried out at atmospheric pressure or underreduced pressure (for example 50 to 100 mbar).

Drying is usually carried out in air at a temperature which can be fromambient temperature, for example 20° C., to a temperature of 100° C.,preferably in the range 50° C. to 90° C.

Drying is continued to constant weight.

It is generally in the range 30 minutes to 12 hours, depending on thetemperature selected.

The spherical agglomerates obtained using the process of the invention,which themselves constitute a further aspect of the invention, have goodmechanical behaviour, attractive flow properties and are easy tomanipulate. Further, they are easy to filter.

In a variation of the process of the invention, it has been discoveredthat 10-phenothiazinylpropanoic acid agglomerates more easily when thepowder to be granulated is first moistened.

Thus 10-phenothiazinylpropanoic acid is thus taken up into an aqueoussuspension.

The quantity of water used to carry out this operation depends on thegranulometry of the starting powder. By way of indication, a quantity ofwater of 500 cm³ to 2000 cm³ is advantageously used per 100 g of10-phenothiazinylpropanoic acid.

The powder and water are preferably brought into contact with stirringfor a period varying, for example, between 5 minutes and 20 minutes.

Thus the moistened powder is separated using any suitable method,preferably by filtering, then the powder obtained undergoes anagglomeration step carried out using the process of the invention.

In a variation of the process of the invention, it has been discoveredthat it may be desirable, before the agglomeration operation of theinvention, to carry out a first adsorption step using at least oneorganic solvent which is preferably slightly soluble in water (forexample less than 5% by weight).

Examples of organic solvents which are suitable for this adsorption stepare aliphatic ethers, preferably isopropyl ether, aliphatic esters,preferably n-propyl or isopropyl acetate, and aromatic hydrocarbonswhich may or may not be halogenated, preferably toluene ormonochlorobenzene.

A mixture of organic solvents can also be used, either successively orsimultaneously, optionally with intermediate steps of separation andresuspension.

The quantity of organic solvent(s) used is not critical and can vary agreat deal. Thus it can represent 1% to 200% by weight of the10-phenothiazinylpropanoic acid, preferably in the range 1% to 10%.

These products are adsorbed by dispersing them in an aqueous suspensionof 10-phenothiazinylpropanoic with vigorous stirring.

The suspension is then separated, preferably by filtering.

The product obtained then undergoes an agglomeration process inaccordance with the invention.

In a variation of the process of the invention, agglomeration can beencouraged by increasing the pH of the suspension of10-phenothiazinylpropanoic acid, preferably to between 4 and 6.

To this end, any appropriate means can be used, more particularly bywashing the starting product one or more times with water.

In a further variation of the process of the invention, which canoptionally replace or supplement the preceding variation, agglomerationcan be carried out in the presence of a mineral salt, preferably with ahigh ionic strength.

Examples of the salts are calcium salts, preferably calcium carbonate orcalcium sulphate, and aluminum salts, preferably aluminium sulphate.Adding a salt encourages agglomeration.

The quantity of salt used is advantageously in the range 0.5% to 5% byweight of the 10-phenothiazinylpropanoic acid.

Thus the process of the invention results in agglomerates in whichagglomeration can be facilitated by initial operations of moisteningusing an aqueous or organic liquid.

Different examples illustrating these implementations of the inventionwill now be given.

The following examples are given by way of illustration and are in noway limiting in nature.

EXAMPLE 1

The 10-phenothiazinylpropanoic acid was agglomerated in two successivesteps Washing operation:

An aqueous suspension of 10% 10-phenothiazinylpropanoic acid (50 g of10-phenothiazinylpropanoic acid in 450 g of water) was stirred at 600revolutions per minute using a Rushton stirrer in a one liter reactorfor 10 minutes.

The operation was carried out at ambient temperature.

The granulometric characteristics of the starting10-phenothiazinylpropanoic acid were as follows:

D₁₀ =0.9 μm;

D₅₀ =3.4 μm;

D₉₀ =12 μm;

The suspension was then filtered through a Buchner funnel then washedwith one liter of water.

The filter cake was used in the next step.

Granulation operation:

This was carried out on 10-phenothiazinylpropanoic acid prepared duringthe preceding operation.

The 10-phenothiazinylpropanoic acid was granulated after adding 31.6 gof isopropyl acetate to the suspension.

After stirring for 2 h 5 minutes at 750 rpm, the agglomerates formedwere oven dried at 70° C. at atmospheric pressure for 2 hours.

The granulometric characteristics of the granules obtained were asfollows:

D₁₀ =881 μm;

D₅₀ =1130 μm;

D₉₀ =1280 μm.

The number of fines was not quantifiable.

EXAMPLE 2

The 10-phenothiazinylpropanoic acid was agglomerated by prior adsorptionof monochlorobenzene onto the 10-phenothiazinylpropanoic acid and byadding calcium carbonate to encourage agglomeration.

Adsorption operation:

The operation was carried out at ambient temperature.

The granulometric characteristics of the starting10-phenothiazinylpropanoic acid were as follows:

D₁₀ =0.9 μm;

D₅₀ =3.4 μm;

D₉₀ =12 μm;

0.5 g of monochlorobenzene was added to an aqueous suspension of 10%10-phenothiazinylpropanoic acid (50 g of 10-phenothiazinylpropanoic acidin 450 g of water) and 10% of isopropyl acetate (50 g) stirred at 600revolutions per minute, using a Rushton stirrer in a one liter reactor.

The system was stirred for 30 minutes.

The contents of the reactor were then filtered.

The filter cake was then washed with 1 liter of water.

Granulation operation:

The filter cake from the preceding experiment was added to 450 g ofwater and 0.3 g of calcium carbonate in the reactor.

The system was stirred for 1 hour. 30 g of isopropyl acetate was thenadded to the reactor.

The system was stirred for 1 hour.

0.2 g of calcium carbonate was then added to the reactor.

Granules with a size of less than one millimeter were then formed afterI hour 30 minutes of stirring.

We claim:
 1. Spherical agglomerates of 10-phenothiazinylpropanoic acid.2. Agglomerates according to claim 1, having a medial diameter (d₅₀) inthe range 50 μm to 3000 μm.
 3. Agglomerates according to claim 1, havinga fines ratio of less than 0.5%.
 4. A process for preparing sphericalagglomerates of 10-phenothiazinylpropanoic acid according to claim 1,comprising stirring a suspension of 10-phenothiazinylpropanoic acid inwater in the presence of a liquid binder which is not miscible withwater comprising esters of aliphatic or cycloaliphatic acids, aliphaticor cycloaliphatic alcohols, or aliphatic or cycloaliphatic ketones.
 5. Aprocess according to claim 4, wherein the aliphatic acid ester comprisesn-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentylor isopentyl acetates.
 6. A process according to claim 5, wherein thenon miscible liquid binder is n-propyl acetate or isopropyl acetate. 7.A process according to claim 4, wherein the aliphatic alcohol comprisesisopentanol or octanol.
 8. A process according to claim 4, wherein theketone used is cyclohexanone.
 9. A process according to claim 4, whereina moistening step is first carried out on the starting powder bybringing the 10-phenothiazinylpropanoic acid into contact with water.10. A process according to claim 4, wherein the10-phenothiazinylpropanoic acid powder undergoes a first adsorption stepusing at least one organic solvent which is slightly soluble in water.11. A process according to claim 10, wherein the organic solvent orsolvents for said adsorption are aliphatic ethers, aliphatic esters, oraromatic hydrocarbons which may or may not be halogenated.
 12. A processaccording to claim 11, wherein a mixture of organic solvents is used,either successively or simultaneously, optionally with intermediatesteps of separation and resuspension.
 13. A process according to claim4, wherein agglomeration is encouraged by increasing the pH of thesuspension.
 14. A process according to claim 4, wherein a mineral saltis added to encourage agglomeration.
 15. A process according to claim14, wherein the added salt comprises calcium salts or aluminium salts.16. Agglomerates according to claim 2, having a medial diameter (d₅₀) inthe range of 200 μm to 1200 μm.
 17. Agglomerates according to claim 16,having a medial diameter (d₅₀) in the range of 500 μm to 1000 μm. 18.Agglomerates according to claim 3, having a fines ratio of less than0.1%.
 19. The process according to claim 9, wherein the10-phenothiazinylpropanoic acid is stirred with water.
 20. The processaccording to claim 11, wherein the aliphatic ester is isopropyl ester,the aliphatic esters comprises n-propyl acetate or isopropyl acetate andthe aromatic hydrocarbons comprise toluene or monochlorobenzene.
 21. Theprocess according to claim 13, wherein the pH of the suspension ispreferably between 4 and
 6. 22. The process according to claim 15,wherein the calcium salts comprise calcium carbonate or calcium sulphateand the aluminum salt is aluminum sulphate.